JP2018537668A - 組織試料での薬物結合分析法 - Google Patents
組織試料での薬物結合分析法 Download PDFInfo
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5082—Supracellular entities, e.g. tissue, organisms
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
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- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
- G01N33/60—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances involving radioactive labelled substances
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- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
- G01N33/6848—Methods of protein analysis involving mass spectrometry
- G01N33/6851—Methods of protein analysis involving laser desorption ionisation mass spectrometry
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- H01—ELECTRIC ELEMENTS
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- H01J49/00—Particle spectrometers or separator tubes
- H01J49/0004—Imaging particle spectrometry
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2458/00—Labels used in chemical analysis of biological material
- G01N2458/15—Non-radioactive isotope labels, e.g. for detection by mass spectrometry
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
Abstract
Description
(1)凍結ヒト悪性黒色腫組織の10マイクロメートル切片の製作を、−20℃で実施した。その後、(2)腫瘍切片を室温でゆっくりと解凍および乾燥することにより試料調製を実施した。その後、切片をメタノールに5分間浸漬し、室温で乾燥した。同様に、リンパ節から切除された凍結ヒト健常組織を同じ方法で処理し、陰性対照として使用した。(3)100nM(ナノモル濃度)の濃度の未標識リガンド、ここではベムラフェニブを使用することにより、1時間にわたって薬物インキュベーションを実施し、そのタンパク質標的に対するリガンド分子の結合を決定した。また、100nM濃度のリガンド、ここではベムラフェニブおよび過剰量の安定同位体標識リガンド、ここにでは13Cベムラフェニブを有する患者腫瘍切片で、同時インキュベーション実験を実施した。滴定実験中、安定同位体標識ベムラフェニブの濃度は、それぞれ、100nM、1μM、10μM、および100μM(マイクロモル濃度)だった。(4)インキュベーション後、切片をPBSで3回洗浄し、その後MilliQ水で連続3回洗浄し、(5)MALDI LTQ−Orbitrap XL機器(Thermo Scientific社、ドイツ)を使用して質量スペクトルを得、orbitrapおよびイオントラップにより化合物シグナルを得た。ImageQuest(Thermo Scientific社、ドイツ)を使用して画像分析を実施した。組織学的分析は、H&E染色、およびBRAF V600Eに対するモノクローナル抗体を使用した免疫組織化学的分析を両方とも実施した。
以下の例は単なる例であり、本発明の範囲を限定するとは決して解釈されるべきでない。むしろ、本発明は、添付の特許請求の範囲によってのみ限定される。
図6では、MSI実験用に処理されたヒト悪性黒色腫組織切片の画像は、組織切片試料の単離細胞堆積形態を示す。がん組織中の薬物(ベムラフェニブ)局在化を特定するために使用されるレーザー脱離質量分析は、組織区画内の空間分解能が30マイクロメートルの分解能で画像をキャプチャするレーザー直径を有する。
Claims (13)
- 置換競合阻害を使用して、組織試料の結合部位に可逆的に結合するリガンドの特異的結合を決定するための方法であって、前記リガンド(未標識)を、標識リガンドの非存在下で第1の組織検体と共にインキュベートするステップ、前記リガンド(未標識)を、標識リガンドの存在下で第2の組織検体と共にインキュベートするステップ、およびその後、前記第1の組織検体および第2の組織検体におけるリガンド局在化を、MALDIイメージング質量分析法を使用して視覚化するステップを含み、前記第1の組織検体および第2の組織検体が、検体の隣接切片である、方法。
- 前記標識リガンドが、重水素標識リガンドまたは13C−同位体標識リガンド等の、同位体で標識されているものである、請求項1に記載の方法。
- 標識リガンドのモル濃度が、置換競合阻害中の前記未標識リガンドのモル濃度より高く、例えば5〜10000倍高い、請求項1または2に記載の方法。
- 前記未標識リガンドが、ナノモル濃度であり、同位体標識リガンドが、マイクロモル濃度である、請求項1〜3のいずれか一項に記載の方法。
- 前記リガンドおよび標識リガンドが同族体である、請求項1〜4のいずれか一項に記載の方法。
- 標的タンパク質の局在化および同位体の結合が、共局在化により確認される、請求項1〜5のいずれか一項に記載の方法。
- リガンドおよび/または標識リガンドが、MALDIイメージング質量分析法を使用して定量化される、請求項1〜6のいずれか一項に記載の方法。
- 前記未標識リガンドを、少なくとも2つの異なる濃度の標識リガンドと共に、組織検体の隣接切片でインキュベートするステップを含む、請求項1〜7のいずれか一項に記載の方法。
- 異なる標識リガンド濃度の滴定を使用するステップを含む、請求項8に記載の方法。
- 前記リガンドおよび/または代謝物および/または標的受容体の動力学的結合特徴が、結合データから算出される、請求項8または9に記載の方法。
- 前記動力学的結合特徴が、Kd、Ki、および/またはIC50である、請求項10に記載の方法。
- 前記リガンドが、最初に(第1の時点で)第2の組織試料に添加され、前記標識リガンドが、後の時点で(第2の時点で)添加される、請求項1〜11のいずれか一項に記載の方法。
- 前記リガンドが、ベムラフェニブであり、前記標識リガンドが、13C−ベムラフェニブである、請求項1〜12のいずれか一項に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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SE1551503 | 2015-11-20 | ||
SE1551503-4 | 2015-11-20 | ||
PCT/EP2016/078131 WO2017085251A1 (en) | 2015-11-20 | 2016-11-18 | Method for drug binding analysis in a tissue sample |
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JP2018537668A true JP2018537668A (ja) | 2018-12-20 |
JP6906515B2 JP6906515B2 (ja) | 2021-07-21 |
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JP2018524264A Active JP6906515B2 (ja) | 2015-11-20 | 2016-11-18 | 組織試料での薬物結合分析法 |
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US (1) | US10718760B2 (ja) |
EP (1) | EP3377894B1 (ja) |
JP (1) | JP6906515B2 (ja) |
KR (1) | KR20180082588A (ja) |
CN (1) | CN108431601B (ja) |
BR (1) | BR112018010156A8 (ja) |
DK (1) | DK3377894T3 (ja) |
ES (1) | ES2781374T3 (ja) |
HK (1) | HK1255013A1 (ja) |
IL (1) | IL259328B (ja) |
WO (1) | WO2017085251A1 (ja) |
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KR102535976B1 (ko) * | 2016-06-13 | 2023-05-23 | 건국대학교 산학협력단 | 형광이미지 및 질량 분석을 이용한 의약품의 생체분포도를 상호보완적으로 확인하는 방법 |
NZ755835A (en) | 2017-01-17 | 2023-12-22 | Heparegenix Gmbh | Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death |
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JP2003503707A (ja) * | 1999-06-25 | 2003-01-28 | インジェネウス コーポレイション | タンパク質またはペプチド間の結合を測定するための蛍光強度法 |
JP2009079046A (ja) * | 2007-09-07 | 2009-04-16 | Kyoto Univ | 化合物、診断薬、核磁気共鳴分析方法、核磁気共鳴イメージング方法、質量分析方法及び質量分析イメージング方法 |
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WO2012126873A1 (en) * | 2011-03-21 | 2012-09-27 | Imabiotech | Method for detecting and quantifying a target molecule in a sample |
WO2013036885A1 (en) * | 2011-09-08 | 2013-03-14 | The Regents Of The University Of California | Metabolic flux measurement, imaging and microscopy |
WO2014128309A1 (en) * | 2013-02-25 | 2014-08-28 | Imabiotech | Method to evaluate the tissue targeting of a molecule of interest |
WO2015038784A1 (en) * | 2013-09-13 | 2015-03-19 | The Board Of Trustees Of The Leland Stanford Junior University | Multiplexed imaging of tissues using mass tags and secondary ion mass spectrometry |
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EP1723178A4 (en) * | 2004-03-12 | 2007-12-12 | Human Genome Sciences Inc | HUMAN G-PROTEIN CHEMOKIN RECEPTOR (CCR5) HDGNR10 |
WO2008154207A1 (en) * | 2007-06-08 | 2008-12-18 | The Burnham Institute For Medical Research | Methods and compounds for regulating apoptosis |
CN102103132B (zh) * | 2009-12-18 | 2013-06-19 | 中国科学院大连化学物理研究所 | 一种从体液代谢组轮廓筛选糖尿病标记物的方法 |
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2016
- 2016-11-18 CN CN201680067740.4A patent/CN108431601B/zh active Active
- 2016-11-18 ES ES16801740T patent/ES2781374T3/es active Active
- 2016-11-18 DK DK16801740.8T patent/DK3377894T3/da active
- 2016-11-18 US US15/777,651 patent/US10718760B2/en active Active
- 2016-11-18 KR KR1020187017419A patent/KR20180082588A/ko not_active Application Discontinuation
- 2016-11-18 EP EP16801740.8A patent/EP3377894B1/en active Active
- 2016-11-18 JP JP2018524264A patent/JP6906515B2/ja active Active
- 2016-11-18 BR BR112018010156A patent/BR112018010156A8/pt unknown
- 2016-11-18 WO PCT/EP2016/078131 patent/WO2017085251A1/en active Application Filing
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2018
- 2018-05-14 IL IL259328A patent/IL259328B/en active IP Right Grant
- 2018-11-06 HK HK18114134.8A patent/HK1255013A1/zh unknown
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JP2003503707A (ja) * | 1999-06-25 | 2003-01-28 | インジェネウス コーポレイション | タンパク質またはペプチド間の結合を測定するための蛍光強度法 |
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Title |
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Also Published As
Publication number | Publication date |
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IL259328B (en) | 2020-06-30 |
KR20180082588A (ko) | 2018-07-18 |
ES2781374T3 (es) | 2020-09-01 |
CN108431601A (zh) | 2018-08-21 |
HK1255013A1 (zh) | 2019-08-02 |
CN108431601B (zh) | 2021-04-27 |
IL259328A (en) | 2018-07-31 |
JP6906515B2 (ja) | 2021-07-21 |
EP3377894A1 (en) | 2018-09-26 |
US20180348210A1 (en) | 2018-12-06 |
DK3377894T3 (da) | 2020-03-23 |
US10718760B2 (en) | 2020-07-21 |
BR112018010156A2 (pt) | 2018-11-21 |
EP3377894B1 (en) | 2019-12-25 |
BR112018010156A8 (pt) | 2019-02-26 |
WO2017085251A1 (en) | 2017-05-26 |
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